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Nodular regenerative hyperplasia (NRH) of the liver is a rare but potentially devastating disease. There is controversy whether these nodules can lead to carcinoma. This disease can be associated with portal hypertension leading to end stage liver disease, requiring a liver transplant.


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Diffuse nodular regenerative hyperplasia of the liver (DNRH). A clinicopathologic study of 24 cases.

Colina F, Alberti N, Solis JA, Martinez-Tello FJ.

Departamento de Anatomia Patologica, Hospital 12 de Octubre, Universidad Complutense, Madrid, Spain.

Liver 1989 Oct;9(5):253-65 Abstract quote

The authors report 24 cases of diffuse nodular regenerative hyperplasia of the liver (DNRH) seen in a General Hospital during the last 9 years (prevalence: 3'1/100,000, incidence: 0'34/100,000).

DNRH was diagnosed in 0.52% of the liver biopsies and 0.72 of the autopsies. These results suggest that DNHR is probably more frequent than suspected, and 1 DNRH was seen for each 39 biopsied cases of liver cirrhosis. Fourteen patients did not have hepatic symptoms. Portal hypertension was present in 9 cases. The biochemical disturbance most frequently found was a moderate elevation of GGT and APh, associated with slight elevation of SGOT, SGPT and bilirubin levels. Normal liver function tests could be seen (3 cases). Previous exposure to potentially hepatotoxic drugs or chemicals was discovered in 15 cases (62.5%). Diseases associated were circulatory disturbances (6 cases), autoimmune disease (5 cases), hemopathies (5 cases), and visceral carcinomas (4 cases). Two patients were recipients of renal transplant.

Nodules distributed through the whole liver tissue were found in 16 cases, while 8 patients showed areas of normal parenchyma in their livers. Impairment of small hepatic vessels was detected in 16 cases. Some uneven cytologic findings were discovered: clusters of small basophilic cells (4 cases), large clear cells (8 cases), and dysplastic hepatocytes (10 cases), which suggests that DNRH could be a preneoplastic condition.

Micronodular transformation (nodular regenerative hyperplasia) of the liver: a report of 64 cases among 2,500 autopsies and a new classification of benign hepatocellular nodules.

Wanless IR.

Department of Pathology, Toronto Western Hospital, Canada.

Hepatology 1990 May;11(5):787-97 Abstract quote

Nodular regenerative hyperplasia is defined by hepatocellular nodules distributed throughout the liver in the absence of fibrous septa between the nodules. Most reports have been single cases so that the prevalence and clinical significance of nodular regenerative hyperplasia is uncertain.

In this study, the hepatic histology of 2,500 consecutive autopsies was reviewed. A spectrum of nodular transformation was found with nodular regenerative hyperplasia present in 2.6% of autopsy livers and qualitatively similar but lesser degrees of nodular transformation in a further 10.2%. Nodular transformation was also seen in 47% of livers with cirrhosis and 69% with incomplete cirrhosis. Obliteration of many small portal veins was seen in all cases with nodular regenerative hyperplasia, but only 4.7% of these had evidence of portal hypertension. The prevalence of various clinical states was compared in nodular regenerative hyperplasia and in controls. The results confirm, extend and quantify the spectrum of associated diseases. Nodular regenerative hyperplasia occurs in 5.6% of individuals over age 80 and with increased frequency in patients with systemic arteritis, polymyalgia rheumatica, massive tumor infiltration and mineral oil deposition. Nodular regenerative hyperplasia appears to be the hepatic analogue of arterial and arteriolar nephrosclerosis.

A new classification of nodular transformation is proposed that encompasses the spectrum of lesions described here and the previously defined entities of focal nodular hyperplasia, partial nodular transformation and "cirrhosis telangiectasia hepatis."

The major conclusion is that nodular regenerative hyperplasia is a secondary and nonspecific tissue adaptation to heterogeneous distribution of blood flow and does not represent a specific entity.



Nodular regenerative hyperplasia of the liver and antiphospholipid antibodies: report of two cases and review of the literature.

Morla RM, Ramos-Casals M, Garcia-Carrasco M, Cervera R, Font J, Bruguera M, Rojas-Rodriguez J, Ingelmo M.

Systemic Autoimmune Diseases Unit, Department of Medicine, IDIBAPS, Hospital Clinic, School of Medicine, University of Barcelona, Catalonia, Spain.

Lupus 1999;8(2):160-3 Abstract quote

Nodular regenerative hyperplasia of the liver (NRHL) is a rare disorder characterized by diffuse micronodular transformation of the hepatic parenchyma without fibrous septa between the nodules. This condition appears to be associated in many occasions with systemic autoimmune diseases.

We describe two new patients with NRHL in whom antiphospholipid antibodies (aPL) were detected in their sera and review the few similar cases reported previously. We also discuss the possible relationship between aPL and NRHL and suggest that these antibodies may play a role in the pathogenesis of some cases of NRHL, specially those with an associated antiphospholipid syndrome.


Nodular regenerative hyperplasia of the liver in Budd-Chiari syndrome: CT and MR features.

Rha SE, Lee MG, Lee YS, Kang GH, Ha HK, Kim PN, Auh YH.

Department of Radiology, University of Ulsan Asan Medical Center, Seoul, South Korea.

Abdom Imaging 2000 May-Jun;25(3):255-8 Abstract quote

We report the imaging findings of spiral computed tomography (CT), magnetic resonance (MR) imaging, and MR angiography in a patient with nodular regenerative hyperplasia of the liver associated with Budd-Chiari syndrome.

Spiral CT showed multiple enhancing nodules during the hepatic arterial and portal venous phases. MR images showed multiple hyperintense nodules on T1-weighted images and hypointense or isointense nodules on T2-weighted images.

MR angiography showed thrombotic occlusion of three hepatic veins, suggesting Budd-Chiari syndrome.


Hepatocellular carcinoma and nodular regenerative hyperplasia: possible pathogenetic relationship.

Nzeako UC, Goodman ZD, Ishak KG.

Division of Hepatic Pathology, Armed Forces Institute of Pathology, Washington D.C., USA.

Am J Gastroenterol 1996 May;91(5):879-84 Abstract quote

OBJECTIVE: In a recent review of hepatocellular carcinoma (HCC) in North American residents, we were surprised to learn that 42.6% of these tumors in the 1980-1993 consultation files of the Armed Forces Institute of Pathology had arisen in noncirrhotic livers. We subsequently noted that the nonneoplastic livers of a number of these had nodular regenerative hyperplasia (NRH), a condition that has been associated with liver cell dysplasia, a putative premalignant lesion. To investigate the possibility that NRH might be a precursor of HCC, we studied those cases in which there was an association of HCC and NRH and examined the possible role of portal vein obstruction in NRH occurring in livers with HCC.

METHODS: Subjects were selected based on study criteria and histological slides, clinical/autopsy records were reviewed, and features of neoplastic and nonneoplastic liver were noted. Simple statistical comparisons were made between the groups with and without NRH with respect to defined variables.

RESULTS: Of 804 patients suitable for study, 342 were noncirrhotic, and 23 of these had NRH. Mean age of patients with NRH was 65 +/- 13.6 (SD) yr. Seventeen of these (73.9%) had liver cell dysplasia, and 16 (69.6%) had portal venous invasion. Liver cell dysplasia occurred in a significantly greater proportion of those with NRH than those without (p < 0.01), but there was no significant difference between both groups with regard to portal venous invasion. Three patients (13%) had received chemotherapy and/or radiotherapy before diagnosis of NRH.

CONCLUSIONS: These findings may be due to the development of HCC within the dysplastic foci that occur in livers with NRH, but the findings do not exclude the converse possibility that NRH may also develop in a noncirrhotic liver with HCC, secondary to portal venous invasion with portal vein occlusion. The temporal relationship between HCC and NRH is probably determined in each case by the particular interaction of multiple pathogenetic factors. Among patients with HCC, factors other than the portal vein obstruction by tumor invasion may play a role in the pathogenesis of NRH.


Nodular regenerative hyperplasia of the liver in a patient with celiac disease.

Riestra S, Dominguez F, Rodrigo L.

Digestive Unit, Hospital Valle del Nalon, Asturias, Spain.

J Clin Gastroenterol 2001 Oct;33(4):323-6 Abstract quote

We present the case of dual adult celiac disease and liver disease with portal hypertension (esophageal varices); a percutaneous liver biopsy was compatible with nonspecific reactive hepatitis. Clinically, celiac disease was characterised by poor response to a gluten-free diet, with the development of a biochemical cholestasis and marked malnutrition.

Our patient died of cerebral hemorrhage, at the age of 50 years, without associated risk factors. The necropsy demonstrated the existence of a nodular regenerative hyperplasia of the liver, splenic atrophy, gelatinous transformation of the bone marrow, and lymphocytic colitis.

We discuss the different types of liver disorders associated with celiac disease and the possible relation between nodular regenerative hyperplasia and celiac disease, based on immunologic mechanisms.


The liver in collagen diseases: pathologic study of 160 cases with particular reference to hepatic arteritis, primary biliary cirrhosis, autoimmune hepatitis and nodular regenerative hyperplasia of the liver.

Matsumoto T, Kobayashi S, Shimizu H, Nakajima M, Watanabe S, Kitami N, Sato N, Abe H, Aoki Y, Hoshi T, Hashimoto H.

First Department of Pathology, Juntendo University, School of Medicine, Japan.

Liver 2000 Oct;20(5):366-73 Abstract quote

AIMS/BACKGROUND: Among patients with collagen diseases, liver enzyme abnormalities are a relatively common phenomenon. To establish the liver pathology in collagen diseases, detailed pathologic studies were performed on the hepatic diseases in many patients, including various kinds of collagen diseases.

METHODS: The livers from 160 patients (120 autopsy and 40 liver biopsy patients) were examined pathologically: 73 with systemic lupus erythematosus (SLE), 32 with rheumatoid arthritis (RA), 18 with polymyositis and dermatomyositis (PM and DM), 15 with systemic sclerosis (SSc), 11 with mixed connective tissue disease (MCTD) and 11 with polyarteritis nodosa (PAN).

RESULTS: Liver diseases were divided into three groups: hepatic arteritis, liver diseases associated with collagen diseases (primary biliary cirrhosis, PBC; autoimmune hepatitis, AIH; nodular regenerative hyperplasia of the liver, NRH) and other liver diseases. Hepatic arteritis presenting the features of the PAN type of necrotizing arteritis was found in 27 autopsy patients. The incidence of arteritis in autopsy patients was 100% in PAN and 8.3-25% in other collagen diseases. Primary biliary cirrhosis was observed in 9 patients, 7 of whom (3 with SSc, 2 with RA, 1 with PM and DM, and 1 with MCTD) had antimitochondrial antibodies (AMA)-positive PBC, and 2 SLE patients had AMA-negative PBC. Three patients (2 with SLE and 1 with MCTD) were diagnosed clinicopathologically as having AIH. However, 3 patients (1 with SLE, 1 with MCTD and 1 with PM and DM) with clinical, biochemical and serologic data indicating probable AIH were excluded from the group with AIH association because of the liver histology (no characteristic features of AIH) and clinical course. These results indicated that data without histologic assessments of the liver are not adequate for diagnosing AIH in collagen diseases. Nodular regenerative hyperplasia of the liver was observed in 7 patients (5 with SLE, 1 with SSc and 1 with PAN).

CONCLUSION: The present study offers data that are useful for the diagnosis and treatment of patients with collagen diseases and liver abnormalities.


Congenital absence of portal vein with nodular regenerative hyperplasia of the liver.

Grazioli L, Alberti D, Olivetti L, Rigamonti W, Codazzi F, Matricardi L, Fugazzola C, Chiesa A.

Department of Radiology, University of Brescia, Spedali Civili, Italy.

Eur Radiol 2000;10(5):820-5 Abstract quote

Congenital absence of the portal vein is a very rare anomaly. The intestinal and splenic venous drainage bypasses the liver and drain into the inferior vena cava (IVC).

Two cases of such anomaly are described. Both cases were investigated by US coupled with echo-colour Doppler examination, CT and MR imaging, followed by digital subtraction angiography (DSA) and liver biopsy.

In the first case the splenic and superior mesenteric vein formed a venous trunk which emptied directly into the IVC; in the second case, the splanchnic blood flowed into a dilated hepatofugal inferior mesenteric vein which connected to the left internal iliac vein. In both cases nodular regenerative hyperplasia of the liver was present, presumably due to an abnormal hepatic cell response to the absent portal flow.

The particular contribution of MR imaging to the diagnosis of both vascular abnormalities and liver parenchyma derangement and its advantages over the other diagnostic techniques is emphasized. The clinical and radiological features of 17 previously reported cases are reviewed.


Nodular regenerative hyperplasia of the liver associated with polyarteritis nodosa.

Nakanuma Y, Ohta G, Sasaki K.

Arch Pathol Lab Med 1984 Feb;108(2):133-5 Abstract quote

Nodular regenerative hyperplasia (NRH) of the liver was found at autopsy in a 74-year-old woman with generalized polyarteritis nodosa.

Such an association is very rare. Small hepatic arteries displayed necrotizing angiitis with thrombotic occlusion of parallel-running portal veins in the portal tracts. Sinusoidal dilatations with an atrophy and occasional dropout of the hepatocytes were often found in the extranodular parenchyma around and between the hyperplastic nodules of hepatocytes.

The arterial, portal venous, and sinusoidal lesions of the liver were prominent in the present case, and all might be contributing factors for the development of NRH of the liver.


A case of Schnitzler's syndrome with nodular regenerative hyperplasia of the liver.

Lauwers A, Chouvy V, Mosnier JF, Misery L, Alexandre C.

Rheumatology Department, Bellevue Hospital, Saint-Etienne, France.

Rev Rhum Engl Ed 1999 May;66(5):281-3 Abstract quote

Schnitzler's syndrome is a rare condition of urticaria, macroglobulinemia, and sclerotic bone lesions.

We report a case in a 70-year-old man in whom inflammatory polyarthralgia was followed by a nonpruritic urticarial eruption with a moderate decline in general health. Laboratory tests showed inflammation and a modest isolated peak of monoclonal IgM kappa. There was no evidence of Waldenstrom macroglobulinemia. Schnitzler's syndrome was considered. However, an ultrasound scan of the abdomen done because of mild gamma-glutamyl-transferase elevation disclosed multiple hepatic lesions. The liver histology showed incipient nodular regenerative hyperplasia. Only about 30 cases of Schnitzler's syndrome have been reported since the seminal description in 1972. Hepatic involvement was a common but nonspecific finding, and we found no cases with nodular regenerative hyperplasia. However, this abnormality is often found in patients with autoimmune or hematological disorders.

The pathogenesis of Schnitzler's syndrome remains unknown, but the possibility of progression to a hematological malignancy requires prolonged follow-up.


Nodular regenerative hyperplasia of the liver and primary Sjogren's syndrome.

Gonzalez-Alvaro I, Carmona-Ortell L, Amigo-Etxenagusia A, Castaneda Sanz S.

Division of Rheumatology, Hospital de La Princesa, Madrid, Spain.

J Rheumatol 1994 Jan;21(1):168-9 Abstract quote

Nodular regenerative hyperplasia (NRH) of the liver is a rare entity associated with autoimmune diseases, hematologic disorders and therapy with immunosuppressive agents.

We describe a patient with primary Sjogren's syndrome and NRH of the liver, the first report of this association. The pathogenesis of NRH is not clear, but the presence of some type of circulatory disorder is suspected.


Nodular regenerative hyperplasia of the liver in systemic lupus erythematosus. The relationship with anticardiolipin antibody and lupus anticoagulant.

Sekiya M, Sekigawa I, Hishikawa T, Iida N, Hashimoto H, Hirose S.

Department of Respiratory Medicine, Juntendo Izunagaoka Hospital, Tokyo, Japan.

Scand J Rheumatol 1997;26(3):215-7 Abstract quote

Recent reports have indicated that nodular regenerative hyperplasia (NRH) associated with systemic lupus erythematosus (SLE) is related to anticardiolipin antibodies (aCL) and/or lupus anticoagulant (LA).

We describe a patient with SLE complicated by NRH, who did not show neither aCL nor LA activity. This case suggests that the pathogenesis of NRH in patients with autoimmune diseases is heterogeneous and not confined to aCL and LA.


Nodular regenerative hyperplasia of the liver in a patient with systemic sclerosis.

Kaburaki J, Kuramochi S, Fujii T, Kuwana M, Tojo T, Ikeda Y, Hosada Y.

Department of Internal Medicine, Keio University School of Medicine, Japan.

Clin Rheumatol 1996 Nov;15(6):613-6 Abstract quote

We report on a 33-year-old female patient with systemic sclerosis and nodular regenerative hyperplasia of the liver (NRHL).

A needle biopsy of the patient's liver did not reveal the histology of NRHL or liver cirrhosis at her first visit to our hospital, when portal hypertension was demonstrated by percutaneous transhepatic portography. After 11 years, the patient died of hepatic and renal failure.

At the time of autopsy, multiple nodules were found in the liver, and a microscopic examination showed a histology compatible with NRHL. It is suggested that the immunological disturbance was related to the patient's portal hypertension and NRHL.

Early Hepatic Nodular Hyperplasia and Submicroscopic Fibrosis Associated With 6-Thioguanine Therapy in Inflammatory Bowel Disease.

Geller SA, Dubinsky MC, Poordad FF, Vasiliauskas EA, Cohen AH, Abreu MT, Tran T, Martin P, Vierling JM, Targan SR.

*Department of Pathology and Laboratory Medicine; daggerDivision of Gastroenterology, Department of Pediatrics; double daggerSection of Hepatology, Division of Gastroenterology, Department of Medicine; and section signDivision of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA.

Am J Surg Pathol. 2004 Sep;28(9):1204-1211. Abstract quote

BACKGROUND: 6-Thioguanine (6-TG) has been used as an alternative thiopurine for inflammatory bowel disease (IBD) patients not responsive to or intolerant of azathioprine (AZA) and 6-mercaptopurine (6-MP). 6-TG-related hepatotoxicity, including liver biochemistry value elevations, sinusoidal collagen deposition on electron microscopy, and veno-occlusive disease, have been described related to its use as therapy for neoplastic disease.

METHODS: We studied 38 liver biopsies from patients treated with 6-TG, almost all of whom (n = 125) received 6-TG for 1 to 3 years at the Inflammatory Bowel Disease Center at Cedars-Sinai Medical Center. All biopsies were fixed in 4% buffered formalin and prepared in the usual manner. Hematoxylin and eosin, Masson's trichrome (trichrome), and reticulin silver impregnation (reticulin) stained slides were studied. In 23 cases, tissue was also prospectively fixed in glutaraldehyde and processed for electron microscopy.

RESULTS: In 20 of the 37 patients studied (53%), nodular regeneration of varying degree was seen with reticulin. In only 4 of these 20 instances (11% of the total) were the changes seen with hematoxylin and eosin and in 3 of the 4, only in retrospect after studying the reticulin preparation. Minimal fibrosis was seen with trichrome in only 13 biopsies (34%), but sinusoidal collagen deposition was observed in 14 of the 23 cases studied with electron microscopy (60%). The biopsy from the 1 patient with nodular hyperplasia obvious with hematoxylin and eosin also demonstrated changes of venous outflow obstruction.

CONCLUSIONS: 6-TG-treated IBD patients are at significant risk for nodular hyperplasia, early fibrosis and, less often, venous outflow disease (Budd-Chiari). The natural history of these changes is unknown and follow-up biopsies are needed to determine histologic and clinical sequela. Patients not demonstrating nodular hyperplasia or fibrosis who continue with 6-TG because there are no better therapeutic choices should be periodically rebiopsied.


Intrasinusoidal cytotoxic CD8+ T cells in nodular regenerative hyperplasia of the liver.

Ziol M, Poirel H, Kountchou GN, Boyer O, Mohand D, Mouthon L, Tepper M, Guillet JG, Guettier C, Raphael M, Beaugrand M.
Hum Pathol. 2004 Oct;35(10):1241-51. Abstract quote  

Diffuse nodular regenerative hyperplasia (NRH) of the liver is an acquired architectural disturbance that can lead to portal hypertension. Although frequently associated with autoimmune or hematologic malignancies, its exact pathogenesis remains largely unknown.

We observed CD8+ cytotoxic T cells in the liver sinusoids of 14 of 44 NRH patients and explored possible relationships between these lymphocytes and vascular damage. The immunophenotype of intrahepatic lymphocytes was determined using immunohistochemical analysis and endothelial injury using the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling method for apoptosis combined with endothelial cell labeling. Controls for the quantitative analysis of liver-infiltrating lymphocytes consisted of patients with chronic hepatitis C or normal liver (n = 13 and n = 6, respectively).

Liver specimens from the 14 patients dislayed intrasinusoidal infiltrate composed of CD3+ and CD8+ lymphocytes, located near atrophic liver cell plates. Significantly more granzyme B+ and CD57+ lymphocytes were observed in NRH than chronic hepatitis C samples with quantitatively similar CD8+ infiltrates. Double-labeling revealed apoptotic endothelial sinusoidal cells in CD8+ T-cell-infiltrated areas in all NRH samples but never in chronic hepatitis C or normal livers. T-cell receptor rearrangement or immunoscope analysis suggested liver-specific polyclonal or oligoclonal T-cell expansions. Clinical and biological characteristics of the 14 patients were similar to those observed in the 30 patients with NRH devoid of lymphocytic infiltration.

We report here that CD8+ cytotoxic T cells infiltrated the liver sinusoids of a high percentage (32%) of NRH patients and suggest that some NRH cases might result from chronic, cytotoxic CD8+ T-lymphocyte targeting of sinusoidal endothelial cells.

Coexpression of IL-6 and soluble IL-6R causes nodular regenerative hyperplasia and adenomas of the liver.

Maione D, Di Carlo E, Li W, Musiani P, Modesti A, Peters M, Rose-John S, Della Rocca C, Tripodi M, Lazzaro D, Taub R, Savino R, Ciliberto G.

Istituto Ricerche di Biologia Molecolare (IRBM) P.Angeletti, Via Pontina Km 30.600, 00400 Pomezia, Rome.

EMBO J 1998 Oct 1;17(19):5588-97 Abstract quote

Studies with tumor necrosis factor p55 receptor- and interleukin-6 (IL-6)-deficient mice have shown that IL-6 is required for hepatocyte proliferation and reconstitution of the liver mass after partial hepatectomy.

The biological activities of IL-6 are potentiated when this cytokine binds soluble forms of its specific receptor subunit (sIL-6R) and the resulting complex interacts with the transmembrane signaling chain gp130.

We show here that double transgenic mice expressing high levels of both human IL-6 and sIL-6R under the control of liver-specific promoters spontaneously develop nodules of hepatocellular hyperplasia around periportal spaces and present signs of sustained hepatocyte proliferation. The resulting picture is identical to that of human nodular regenerative hyperplasia, a condition frequently associated with immunological and myeloproliferative disorders. In high expressors, hyperplastic lesions progress with time into discrete liver adenomas.

These data strongly suggest that the IL-6/sIL-6R complex is both a primary stimulus to hepatocyte proliferation and a pathogenic factor of hepatocellular transformation.


Hepatic hemodynamics in a patient with nodular regenerative hyperplasia.

Ueno S, Tanabe G, Sueyoshi K, Yoshinaka H, Yamamoto S, Kurita K, Yoshidome S, Nuruki K, Aikou T.

First Department of Surgery, Kagoshima University School of Medicine, Japan.

Am J Gastroenterol 1996 May;91(5):1012-5 Abstract quote

Nodular regenerative hyperplasia of the liver is an uncommon condition. Approximately 50% of these patients develop portal hypertension. Few previous reports document the site of increased resistance to blood flow within the liver in this disorder.

We measured Doppler waveform patterns of the right hepatic vein by pulsed Doppler ultrasonography and portal, wedged hepatic, and free hepatic venous pressure by intravenous catheter before and after splenectomy in a 47-yr-old woman with nodular regenerative hyperplasia who presented with portal hypertension and pancytopenia. Nodular regenerative hyperplasia was histologically confirmed. Pre- and postoperative measures indicated a marked difference between wedged hepatic venous pressure and free hepatic venous pressure, whereas there was little difference between portal venous pressure and wedged hepatic venous pressure. Doppler waveform patterns of the right hepatic vein showed an unclear pulsatile flow pattern with a decreasing reversed phase.

The above data suggest that portal hypertension in nodular regenerative hyperplasia is primarily sinusoidal, similar to that seen with cirrhosis.




MR imaging of hepatic nodular regenerative hyperplasia.

Siegelman ES, Outwater EK, Furth EE, Rubin R.

Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia 19104, USA.

J Magn Reson Imaging 1995 Nov-Dec;5(6):730-2 Abstract quote

Nodular regenerative hyperplasia (NRH), a rare condition that is commonly associated with noncirrhotic portal hypertension, is not well described in the MR literature.

Three patients at two institutions were identified who had both abdominal MR imaging and pathologic evidence of NRH. All examinations were performed at 1.5 T and included axial T1- and T2-weighted spin-echo (SE) images. The MR studies were reviewed by two radiologists in consensus. Two patients had multiple liver lesions that had high signal components on T1-weighted images and were predominantly isointense with liver on the T2-weighted images.

One patient had no focal lesions identified. NRH, when visualized on MR images, appears as multifocal masses with shortened T1 and T2 similar to liver. NRH should be considered in the differential diagnosis of hepatocellular tumors, especially in patients with a predisposing condition.

Pseudotumoral presentation of nodular regenerative hyperplasia of the liver: imaging in five patients including MR imaging.

Casillas C, Marti-Bonmati L, Galant J.

Department of Radiology, Hospital Dr. Peset, E-46 017 Valencia, Spain.

Eur Radiol 1997;7(5):654-8 Abstract quote

Nodular regenerative hyperplasia (NRH) of the liver is a condition characterized by multiple monoacinar regenerative nodules in the absence of fibrous septa. When these nodules become confluent they may be seen with sonography or CT. The appearance of these pseudotumoral pattern of NRH has been scarcely described with MRI.

We present the imaging findings of five patients with NRH and a pseudotumoral form at sonography. Sonography depicted hyperechoic lesions in four patients and hypoechoic lesions in another. Computed tomography showed hypodense lesions with little contrast enhancement in two patients. Three patients showed subtle focal liver lesions on MRI: isointense in one, mildly hypointense in another, and minimally hyperintense in a patient with siderosis.

The dynamic behavior at MRI was similar to the normal liver parenchyma. Hyperechoic lesions on sonography or hypodense lesions on CT, barely or not seen on MRI, can be indicative of NRH in an appropriate clinical setting.

Imaging features of nodular regenerative hyperplasia of the liver mimicking hepatic metastases.

Clouet M, Boulay I, Boudiaf M, Soyer P, Nemeth J, Kiselman R, Rymer R.

Department of Radiology, Institut Curie, 26 rue d'Ulm, 75231 Paris Cedex 05, France.

Abdom Imaging 1999 May-Jun;24(3):258-61 Abstract quote

We described the sonographic, computed tomographic (CT), and magnetic resonance (MR) imaging features of one atypical case of nodular regenerative hyperplasia of the liver. The presence of multiple hepatic nodules suggested the diagnosis of metastatic disease to the liver because of a peripheral rim of enhancement on CT obtained after intravenous administration of contrast material and a halo sign on T2-weighted spin-echo MR imaging. Examination of the pathologic specimen obtained after surgical biopsy showed that the nodules were made of hepatocytes, with a nodular arrangement surrounded by peliosis, without fibrosis or cirrhosis.

These findings suggested that peliosis may cause peripheral rim of enhancement on CT and halo sign on MR imaging. In light of this case, nodular regenerative hyperplasia of the liver should be considered in the differential diagnosis of hepatic metastases.

Nodular regenerative hyperplasia of the liver: SPECT evaluation with Tc-99m stannous colloid and Tc-99m neoglycoalbumin

Yamamoto W, Shuke N, Saito Y, Usui K, Komura K, Ishizaki A, Ojima H, Aburano T.

Department of Radiology, Asahikawa Medical College Hospital, Japan.

Clin Nucl Med 1999 Oct;24(10):806-8




Nodular regenerative hyperplasia of the liver. A review of 14 cases.

Arvanitaki M, Adler M.

Service de Hepatogastroenterologie, Universite Libre de Bruxelles, Hopital Erasme, Brussels, Belgium.

Hepatogastroenterology 2001 Sep-Oct;48(41):1425-9 Abstract quote

BACKGROUND/AIMS: Nodular regenerative hyperplasia of the liver, is a noncirrhotic liver disease, characterized by nodules in the hepatic parenchyma, which clinically presents primarily with manifestations of portal hypertension. The aims of this study are i) to review the clinical, histological and diagnostic aspects of 14 documented cases of NRHL, and ii) to assess the evolution and management of this condition in the cases reviewed.

METHODOLOGY: The diagnosis of nodular regenerative hyperplasia of the liver was based on liver biopsy in all cases. Imaging studies (ultrasonography, computed tomography scan and magnetic resonance imaging scan) were performed as part of the diagnostic evaluation. Clinical manifestations and biochemical tests were recorded at the time of diagnosis. Management and prognosis were also reviewed.

RESULTS: The most common clinical manifestations were those of portal hypertension, namely splenomegaly, esophageal varices and variceal bleeding. The histological findings were nodules in the hepatic parenchyma, the typical histologic feature of nodular regenerative hyperplasia of the liver, with mild periportal fibrosis and intraportal lymphocytic infiltration. Biochemical tests showed normal synthetic liver function, as evidenced by normal serum albumin, bilirubin and prothrombin time. Elevation of gamma-glutamyl transpeptidase and alkaline phosphatase due to cholestasis was noted. Management was directed to portal hypertension and variceal bleeding, with beta-blockers, sclerotherapy, mesenteric-caval shunt and transjugular intrahepatic portosystemic shunt with satisfactory results.

CONCLUSIONS: Nodular regenerative hyperplasia of the liver is an uncommon condition but it should be considered in patients with unexplained portal hypertension and distinguished from liver cirrhosis, in view of the differences in the natural history and prognosis. Liver biopsy confirms the diagnosis. Management is directed primarily to portal hypertension and variceal bleeding, which is the main source of mortality. Liver failure is uncommon due to satisfactory preservation of liver function.


Familial occurrence of nodular regenerative hyperplasia of the liver: a report on three families.

Dumortier J, Boillot O, Chevallier M, Berger F, Potier P, Valette PJ, Paliard P, Scoazec JY.

Federation des Specialites Digestives, Hopital Edouard Herriot, Lyon, France.

Gut 1999 Aug;45(2):289-94 Abstract quote

BACKGROUND/AIMS: Nodular regenerative hyperplasia of the liver is a histological lesion usually associated with systemic diseases, haematological malignancies, or drugs. Its prognosis depends on portal hypertension, which usually is well tolerated and requires medical management only.

PATIENTS: Three unrelated families, in which two sibling adult male patients presented with nodular regenerative hyperplasia of the liver, were studied.

METHODS: Complete clinical charts and liver biopsy specimens were available for all patients. In addition, explanted livers were available for examination for the two transplanted patients.

RESULTS: There was no evidence of any of the various clinical situations known to be associated with nodular regenerative hyperplasia of the liver. Portal hypertension was severe, requiring surgical treatment in two cases. Renal lesions were present in three patients. In two patients, progressive evolution to liver atrophy and hepatic failure, associated with renal failure, led to combined liver and renal transplantation.

CONCLUSIONS: This report describes the existence of familial cases of nodular regenerative hyperplasia of the liver, occurring without underlying or associated systemic disease, characterised by a poor clinical course and often associated with progressive renal failure.


Nodular regenerative hyperplasia of the liver in children.

Moran CA, Mullick FG, Ishak KG.

Department of Environmental and Drug-Induced Pathology, Armed Forces Institute of Pathology, Washington, D.C. 20306-6000.

Am J Surg Pathol 1991 May;15(5):449-54 Abstract quote

Sixteen cases of nodular regenerative hyperplasia of the liver in children are presented. The patients, 10 girls and 6 boys, were between the ages of 7 months and 13 years, with a median of 6 years. Clinically, nine children presented with hepatomegaly or splenomegaly, with and without signs of portal hypertension. A history of anticonvulsant drug therapy was obtained in four patients. Associated conditions in the remaining three cases were Donohue's syndrome, disseminated intravascular coagulation, and angiomyolipoma of the kidney.

In five patients a clinical diagnosis of primary intra-abdominal tumor was made. Follow-up showed that six patients died of causes unrelated to the nodular hyperplasia. Two patients were asymptomatic when last seen 5 and 18 years after the initial diagnosis of nodular hyperplasia. Both patients underwent shunt surgery.

No follow-up was available for eight patients. The importance of recognizing this entity in the pediatric age group, as well as its histopathologic differential diagnosis, is stressed.

Nodular regenerative hyperplasia of the liver: case report of a 13-year-old girl and review of the literature.

Trenschel GM, Schubert A, Dries V, Benz-Bohm G.

Department of Diagnostic Radiology, Paediatric Radiology, University of Cologne Medical School, Kerpener Strasse 68, D-50924 Cologne, Germany.

Pediatr Radiol 2000 Jan;30(1):64-8 Abstract quote

BACKGROUND: Nodular regenerative hyperplasia (NRH) of the liver is a multi-acinar regenerative nodular lesion in a non-cirrhotic liver. It is a rare entity, especially in children, and remains of unknown aetiology.

OBJECTIVE: NRH is often seen in association with other diseases or drug intake. In half of patients it is complicated by portal hypertension. Radiologically, its nodular appearance may look like neoplasia.

RESULTS: We report a case of NRH with enormous hepatomegaly and multiple huge nodules.

CONCLUSION: We wish to emphasise the importance of open wedge biopsy to establish diagnosis, since the prognosis of NRH in the absence of portal hypertension is good. Complications such as rupture of a nodule are rare.



Nodular regenerative hyperplasia of the liver. Report of three cases and review of the literature.

Miyai K, Bonin ML.

Am J Clin Pathol 1980 Feb;73(2):267-71 Abstract quote

Nodular regenerative hyperplasia of the liver is characterized grossly by diffusely nodular liver resembling micronodular cirrhosis.

Viewed microscopically, the nodules consist of regenerative parenchyma without fibrosis, which are usually smaller than the hepatic lobule.

Nodular regenerative hyperplasia is distinct from other nodular lesions of the liver such as cirrhosis, partial nodular transformation, focal nodular hyperplasia, and adenoma. Although nodular regenerative hyperplasia is seldom reported, it may occur more frequently than it is recognized.



Use of alpha-1-antitrypsin staining in the diagnosis of nodular regenerative hyperplasia of the liver.

Nakhleh RE, Snover DC.

Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis.

Hum Pathol 1988 Sep;19(9):1048-52 Abstract quote

Nodular regenerative hyperplasia (NRH) is a disorder characterized by regenerative nodules scattered diffusely throughout the liver without associated fibrosis. It is most often recognized at autopsy when the entire liver is available for inspection. The diagnosis of NRH by needle biopsy is much more subtle.

Since alpha-1-antitrypsin (AAT) expression by hepatocytes in a variety of liver diseases has suggested that it may represent a marker for regenerative or damaged hepatocytes, we elected to study the expression of AAT by immunohistochemical staining of paraffin-embedded tissue of biopsy material as a possible marker of this diagnosis. Seventeen biopsies of the liver showing histologic features consistent with NRH were selected and compared with 20 biopsies of the liver without features of NRH. Eight of the NRH cases showed periportal granular AAT staining as opposed to only one of the non-NRH biopsies (P less than .01; Fisher exact test).

These results indicate that AAT expression is increased in the regenerating compartment (as opposed to the presumably damaged atrophic portion) of the liver in NRH and suggest that AAT staining may be useful in confirming the biopsy diagnosis of NRH.


p53 immunoreactivity in hepatocellular adenoma, focal nodular hyperplasia, cirrhosis and hepatocellular carcinoma.

Ojanguren I, Ariza A, Castella EM, Fernandez-Vasalo A, Mate JL, Navas-Palacios JJ.

Department of Anatomic Pathology, Hospital Universitari Germans Trias i Pujol, Barcelona, Spain.

Histopathology 1995 Jan;26(1):63-8 Abstract quote

The prolonged half-life of mutant p53 makes feasible its immunocytochemical detection. In order to assess the pathogenetic role of mutant p53 in regenerative and neoplastic liver disease we studied its immunohistochemical expression in cases of hepatic cirrhosis, hepatocellular carcinoma (HCC), cirrhosis with areas of HCC, hepatocellular adenoma and focal nodular hyperplasia.

The study included needle and wedge biopsies of 50 cirrhotic livers, 59 HCCs (36 of them with associated cirrhosis), six adenomas and two focal nodular hyperplasias. Sixty-five HCC fine-needle cytology specimens were also included in the study. There was no immunohistochemical evidence of mutant p53 expression in any of the cases of cirrhotic liver (except for one instance associated with HCC) adenoma or focal nodular hyperplasia. In contrast p53 was detected in 8.5% of HCC cases in the biopsy series and 24% of HCC cases in the fine needle aspiration series. In addition, mutant p53 expression in HCC was positively correlated with tumour grade. According to grade, the distribution of p53 positive immunoreactivity among HCCs was as follows: Grade I-II, 0% of cases in the biopsy series and 9% in the fine needle aspirates; Grade III, 18% in the biopsy series and 55% in the fine needle aspirates; and Grade IV, 40% in the biopsy series.

Therefore, mutant p53 expression does not seem to be associated with benign liver lesions but seems to correlate with the progression of HCC through various grades of increasing malignancy.


CIRRHOSIS Regenerative nodules



Results of liver transplantation for nodular regenerative hyperplasia.

Radomski JS, Chojnacki KA, Moritz MJ, Rubin R, Armenti VT, Wilson GA, Herrine S, Conn M.

Department of Surgery, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.

Am Surg 2000 Nov;66(11):1067-70 Abstract quote

Liver transplantation has been performed in individuals with a pretransplant clinical diagnosis of cirrhosis but with nodular regenerative hyperplasia histologically. The purpose of this report is to investigate the results of liver transplantation in patients proven to have nodular regenerative hyperplasia post-transplant.

A retrospective review was undertaken of four patients who underwent liver transplantation with a histologic diagnosis of nodular regenerative hyperplasia. All were felt to be cirrhotic on clinical grounds. Final histology of the explanted liver was confirmed by a single pathologist. Their ages ranged from 39 to 54 years, and three of the four were male. Three had pretransplant needle liver biopsies, two percutaneous and one transjugular. All revealed nonspecific reactive changes.

Ultrasound and MRI were interpreted as consistent with cirrhosis in four of four and three of four cases, respectively. Portal vein flow was hepatopedal in three and absent in one. Pretransplant clinical characteristics and frequency were as follows: bleeding varices two, clinical ascites three, encephalopathy three, and impaired hepatic synthetic function two. All four patients underwent successful liver transplantation. There were no episodes of acute rejection. All are alive and well with normal graft function 2 to 4 years post-transplant.

We conclude the following. 1) Patients with clinical end-stage liver disease due to underlying nodular regenerative hyperplasia can successfully undergo transplantation. 2) Nodular regenerative hyperplasia can present with signs and symptoms of liver failure, is difficult to diagnose by needle biopsy, and can be difficult to discriminate clinically from cirrhosis. 3) Although each case must be individually evaluated transplantation may be the optimal therapy in patients presenting with complications of liver failure.

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Sixth Edition. WB Saunders 1999.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

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